EP0526695B1 - Solutions de PVP-I stabilisées - Google Patents

Solutions de PVP-I stabilisées Download PDF

Info

Publication number
EP0526695B1
EP0526695B1 EP92106500A EP92106500A EP0526695B1 EP 0526695 B1 EP0526695 B1 EP 0526695B1 EP 92106500 A EP92106500 A EP 92106500A EP 92106500 A EP92106500 A EP 92106500A EP 0526695 B1 EP0526695 B1 EP 0526695B1
Authority
EP
European Patent Office
Prior art keywords
solution
iodine
pvp
solutions
iodophor
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
EP92106500A
Other languages
German (de)
English (en)
Other versions
EP0526695A1 (fr
Inventor
Dileep Bhagwat
Benjamin Oshlack
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Euro Celtique SA
Original Assignee
Euro Celtique SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Euro Celtique SA filed Critical Euro Celtique SA
Publication of EP0526695A1 publication Critical patent/EP0526695A1/fr
Application granted granted Critical
Publication of EP0526695B1 publication Critical patent/EP0526695B1/fr
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/18—Iodine; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/74—Synthetic polymeric materials
    • A61K31/785—Polymers containing nitrogen
    • A61K31/787—Polymers containing nitrogen containing heterocyclic rings having nitrogen as a ring hetero atom
    • A61K31/79—Polymers of vinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/58—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • the present invention is related to stabilized povidone-iodine solutions and a novel method of preparing the same.
  • the present invention is further related to microbicidal ophthalmic preparations comprising povidone-iodine.
  • Povidone-iodine polyvinylpyrrolidine-iodine or PVP-I
  • U.S.P. U.S. Pharmacopeia
  • PVP-I polyvinylpyrrolidine-iodine
  • U.S.P. U.S. Pharmacopeia
  • Povidone-iodine is a complex of iodine with povidone. It contains not less than 9.0% by weight, and not more than 12% by weight of available-iodine (titratable iodine) calculated on a dry basis.
  • Povidone Iodine USP has a specification for iodine ion of not more than 6.6% by weight on a dry basis.
  • PVP-I solutions as well as other iodophor solutions, have been packaged for medicinal use, e.g. in soft plastic bottles or containers, which can be used for various medicinal purposes, e.g. douching.
  • elemental iodine equilibrium iodine
  • the iodophor solution itself preferably comprises about 0.01-0.03% of iodide therein, in addition to the additional amount of iodide that has been introduced which improves the stability of the iodophor and minimizes leaching of iodine through the packaging.
  • the additional iodide is preferably KI.
  • PVP-I solutions are known to exert microbicidal activity, stabilizing PVP-I solutions for ophthalmic use was problematic prior to the present invention, and in view of the stability problems associated with dilute PVP-I solutions, it has not been possible to date to provide an acceptable formulation of dilute PVP-I solutions, such as for ophthalmic use.
  • the introduction of donating species such as iodate into a PVP-I solution is not considered to be desirable when the solution is to be used as an ophthalmic preparation because iodate (and probably iodide) are known to be irritating and toxic to the pigment epithelium of the retina.
  • a PVP-I solution stabilized via the addition of, for example, potassium iodide and/or potassium iodate would not be useful as an ophthalmic preparation.
  • an ophthalmic solution should have the same pH as human lacrimal fluid. Such a result can be obtained for an ophthalmic preparation via the use of a buffer system approaching physiological pH. It is common practice to control the pH of solutions through the use of buffers, which are pairs of related chemical compounds capable of resisting large changes in the pH of a solution caused by the addition of small amounts of acid or base, regardless of the source. For example, borate buffers (which comprise weak acids and their conjugate bases) have been used in ophthalmic preparations.
  • PVP-I solutions have been buffered to at least a pH of 5 to maintain stability. This prior art is a known requirement for stability of aqueous PVP-I solutions. It has also long been recognized in the art that the more dilute the PVP-I solution, the less stable it is.
  • the present invention is related to stabilized, microbicidal iodophor solutions which can be stored in glass containers.
  • the present invention is related to a iodophor solution stable according to U.S.P. standards comprising a microbicidal effective amount of available iodine which amount is insufficient by itself to render the iodophor solution stable according to U.S.P. standards, and a suitable alkalinizing agent in an amount effective to maintain said amount of available iodine at a minimum of about 85% and a maximum of 120% of an initial amount of available iodine in the solution for about three months at a temperature of about 40°C when said solution is stored in a glass container, the solution being non-buffered.
  • the iodophor solution comprises a non-irritating ophthalmic solution which is microbicidal and stable according to U.S.P. standards but which solution is not buffered.
  • the alkalinizing agent in the effective amount is non-toxic and non-irritating to the eye.
  • a sufficient amount of an agent is included to render the solution substantially isotonic to human lacrimal fluid.
  • the iodophor solution comprises povidone-iodine.
  • the present invention is related to a substantially non-irritating povidone-iodine ophthalmic solution comprising povidone-iodine in an initial amount of available iodine of from about 0.03% to about 0.06%, which solution is microbicidal and non-buffered.
  • the present invention is further related to an iodophor solution stable according to U.S.P. standards, comprising a microbicidal effective amount of available iodine which is insufficient by itself to render said iodophor solution stable according to U.S.P. standards, and an alkalinizing agent in an amount effective to provide said solution with an initial pH of from about 2 to about 6.5, such that the solution is stable according to U.S.P. standards, the solution being non-buffered.
  • U.S.P. standards comprising a microbicidal effective amount of available iodine which is insufficient by itself to render said iodophor solution stable according to U.S.P. standards, and an alkalinizing agent in an amount effective to provide said solution with an initial pH of from about 2 to about 6.5, such that the solution is stable according to U.S.P. standards, the solution being non-buffered.
  • the present invention is also related to a method of preparing a povidone-iodine solution which is stable according to U.S.P. standards when stored in a glass container.
  • povidone-iodine is provided in an effective amount of available iodine to render the solution microbicidal.
  • a suitable alkalinizing agent is added in an amount effective to maintain the amount of available iodine at a minimum of about 85% and a maximum of 120% of an initial amount of said available iodine for about three months at a temperature of about 40°C when the ophthalmic solution is stored in a glass container, and the solution is non-buffered.
  • the povidone iodine solution is intended for use as an ophthalmic preparation, and the alkalinizing agent in the said effective amount is non-toxic and non-irritating.
  • the present invention is also related to a process for treating the eye with a microbicidal treatment which is stable according to U.S.P. standards.
  • a povidone-iodine solution having an effective amount of available iodine to render the solution microbicidal but which in said amount is by itself insufficient to render the solution stable according to U.S.P. standards is prepared, and a suitable alkalinizing agent is added in an amount effective to maintain said amount of available iodine at a minimum of about 85% and a maximum of 120% of an initial amount of said available iodine for about three months at a temperature of about 40°C.
  • the alkalinizing agent in the said effective amount is non-toxic and non-irritating, and the solution is non-buffered.
  • the solution is rendered substantially isotonic to human lacrimal fluid, and stored in a glass container for at least three weeks. Thereafter, the eye is treated with the microbicidal solution by placing a sufficient amount of the solution onto the external
  • iodophor The combination of elemental iodine and certain organic polymers, e.g. polyvinylpyrrolidone and detergent polymers, have been termed iodophor.
  • the organic polymers used to form an iodophor comprise a broad range of molecular weight and chain length, and may be either ionic or non-ionic in characters, as well as possessing either surfactant or non-surfactant properties.
  • a loose bond forms between the iodine and organic polymer to form a complex.
  • Aqueous solutions of up to about 30% in iodine content may be prepared.
  • the general method for the preparation of a iodophor complex is to bring into intimate contact, elemental diatomic iodine with the selected polymer, either in the dry or powder form or in the presence of a suitable solvent. Heat may be used to accelerate complex formation. Upon completion of the reaction, the iodophor complex of the respective polymeric carrier with iodine is obtained in certain reproducible proportions of one to the other.
  • the iodophor preparation can then be introduced in any convenient manner into the appropriate packaging, for purposes of the present invention, preferably glass containers (e.g., bottles).
  • the present invention is applicable to any iodine-releasing material.
  • the iodine-releasing material must of course be one that is suitable, i.e., non-toxic and non-irritating.
  • iodophor complexes comprise non-ionic, cationic and anionic detergent carriers.
  • non-ionic, cationic and anionic detergent carriers are examples of non-ionic, cationic and anionic detergent carriers.
  • iodide salts which can be added to such iodophor preparations include sodium iodide, potassium iodide, calcium iodide and zinc iodide, with potassium iodide specifically being preferred.
  • Iodophor preparations are described in terms of available or titratable iodine which is considered to be the iodine released from the complex to exert germicidal action thereof. However, such available iodine determinations do not reflect either the total iodine content of the iodophor, or its germicidal potency.
  • the iodine moiety of polyvinylpyrrolidone (povidone)-iodine complex is present in an aqueous iodophor solution in the form of different thermodynamically stable anionic iodine species and diatomic iodine.
  • the anionic iodine forms are capable of generating diatomic iodine in the course of their respective equilibrium reactions.
  • the anionic species do not distribute themselves into an extracting solvent which removes only the nonionic iodine. Such iodine is generated in the course of the iodine equilibrium reaction and extraction thereof by a solvent fractionates the equilibrium state. The disturbed equilibrium reaction is soon re-established to restore new anionic iodine species, but now at a different concentration level since the previous aqueous iodine content of the solution has been reduced by the extracting solvent.
  • iodophor iodine exerting microbicidal actions exists in solutions in dynamic equilibrium with ionic iodine species, removal of one or more of the iodine species results in formations of new equilibrium forms.
  • An extracting solvent removes or consumes iodine from the iodophor solution in a manner similar to that of a microbial and organic load during degerming use of the iodophor solution.
  • the amount of iodine available for germicidal action in an iodophor preparation therefore is the amount of iodine in equilibrium in the solution at the time of use.
  • Such equilibrium iodine content represents the germicidal potency of the preparation, but not the total iodine content titrated for the preparation nor the apparent distribution of the iodine forms.
  • iodophor solutions have been assayed in the art for available or titratable iodine, it is the equilibrium iodine which is the particular form of iodine present in the iodophor solution that is instantly available to exert microbicidal action.
  • This form of iodine differs from titratable iodine and the other iodine species present in the iodophor solution. Therefore, the equilibrium iodine content of an iodophor solution is to be distinguished from its titratable iodine content.
  • the titratable iodine content of an iodophor preparation includes the iodine reservoir of the iodophor preparation (povidone iodine), as well as the equilibrium iodine in solution.
  • Titratable iodine Reservoir Iodine + Equilibrium Iodine
  • the level of iodine ions inherently present in any PVP-I formulation using PVP-I raw material therefore depends on the amount of iodine ion present in the raw material PVP-I used. For example, on a theoretical basis, if the PVP-I contains 6% by weight iodine ion, then a formulation containing 10% by weight of PVP-I would contain 0.6% by weight iodine ions.
  • PVP-I raw material containing a level of iodide ion greater than specification of U.S. Pharmacopeia could also be used in formulating a PVP-I containing product.
  • the minimum amount of iodide ion inherently present in a PVP-I formulation could be as low as 0.0% by weight, while the maximum amount of iodide ion inherently present in such a PVP-I formulation would be the amount contributed by the PVP-I raw material used to formulate the same. For example, on a theoretical basis, if a formulation contains 0.36% by weight PVP-I, and the PVP-I contains the maximum iodide allowable of 6.6% by weight, then the formulation will have 0.0237% by weight iodide present.
  • the U.S. Pharmacopeia U.S.P.
  • U.S.P. U.S. Pharmacopeia
  • the maximum allowable limit is 0.36% PVP-I and the minimum is 0.25%.
  • stability of a 0.30% solution should be above 0.25% PVP-I (or 0.25% available iodine) to be considered stable.
  • PVP-I solutions having a concentration greater than 1.0% are relatively stable.
  • concentration of PVP-I is not suitable for many uses.
  • a concentration of PVP-I of 1.0% or greater is not desirable in ophthalmic preparations because such concentrations are irritating to the eye.
  • the PVP-I solution has a minimum concentration of 0.3% (0.03% available iodine) in order to maintain the stability of the solution according to U.S.P. stability standards. It has now surprisingly been further found that lower PVP-I concentrations, even as low as 0.2%, are as effective as known marketed products such as Neosporin and Garamycin eye drops, and that PVP-I solutions having concentrations as low as 0.12% (0.012% available iodine) are also effective as anti-microbials. Although at such concentrations the iodophor solutions of the present invention are not stable according to U.S.P. standards, the iodophor solutions of the present invention at such concentrations are surprisingly and substantially more stable than prior art iodophor solutions at such concentrations, and therefore are useful nonetheless where compliance with U.S.P. standards is not of concern.
  • the stabilized microbicidal solutions of the present invention preferably comprise from about 0.12% to about 0.72% PVP-I.
  • a higher concentration of PVP-I may be used, the limiting factor, among other things, being that the ophthalmic solution should not be unduly irritating to the eye.
  • the limiting factor for lower concentrations of PVP-I solutions, among other things, is stability and efficacy as a microbicidal.
  • the PVP-I solutions of the present invention are stabilized by adding a suitable alkalinizing agent.
  • the amount of alkalinizing agent needed is that amount which is effective to maintain the amount of available iodine at a minimum of about 85% and a maximum of 120% of an initial amount of said available iodine for about three months at a temperature of about 40°C when the solution is stored in a glass container.
  • the solution is non-buffered.
  • the alkalinizing agent in the said effective amount is non-toxic and preferably non-irritating. Any such alkalinizing agent known in the art which may be used in ophthalmic preparations in the said effective amount may be used in the present invention.
  • the alkalinizing agent preferably comprises sodium hydroxide, potassium hydroxide, sodium bicarbonate, disodium phosphate, mixtures of any of the foregoing, or the like.
  • An especially preferred alkalinizing agent is sodium hydroxide.
  • the choice of alkalinizing agent is, of course, not as critical with respect to toxicity and irritating properties.
  • any alkalinizing agent known in the art may be used, depending upon the intended use of the product.
  • the pH of a dilute PVP-I solution i.e. a PVP-I solution having a concentration of 1.0% or less is lower than pH 2, depending upon the concentration of the PVP-I.
  • the pH of the PVP-I solution is adjusted via the addition of the alkalinizing agent until a pH of from about 2 to about 6.5 is attained, preferably at least until a stabilized product is obtained according to U.S.P. standards. More preferably, the alkalinizing agent is added to the PVP-I solution until a pH of from about 2 to about 4.5 is obtained. It is especially preferred that the alkalinizing agent (i.e., sodium hydroxide) is added in an amount effective to adjust the pH of the PVP-I solution to a pH of from about 4 to about 4.5.
  • the alkalinizing agent i.e., sodium hydroxide
  • the pH of normal tear (lacrimal) fluid is about 7.4, although the pH of the film of tears in contact with the surface of the eye may higher, i.e. from 7.4-8.0, because of loss of carbon dioxide to the atmosphere. It has been reported that an uncomfortable condition exists when the pH is under 6 or over 8, but the eye is more sensitive to acid than to alkaline solutions. The eye has also been reported to tolerate isotonic solutions more alkaline than tear fluid better than it does isotonic solutions that are acid.
  • the tear fluid itself has a certain buffer capacity, although it is not sufficiently strong to avoid discomfort when solutions of more strongly acidic drugs are applied.
  • the stabilized, microbicidal PVP-I ophthalmic solutions of the present invention are substantially non-irritating to the eye despite the fact that these solutions are not buffered and generally have a pH in the acidic range, e.g. pH 4.
  • Lacrimal fluid has an isotonicity value approximately the same as that of a 0.9% sodium chloride solution.
  • An ophthalmic solution which is isotonic with lacrimal fluid causes less discomfort than one that is hypotonic or hypertonic. It is therefore especially preferred that the ophthalmic preparations of the present invention be adjusted with a suitable agent so that they are isotonic with the eye (i.e., with human lacrimal fluid).
  • An especially preferred agent is sodium chloride.
  • Antimicrobials are usually required in ophthalmic solutions.
  • a suitable antimicrobial preservative should have a wide bacteriostatic, or bacteriocidal activity against organisms; must maintain its microbial properties during storage, etc. have a rapid action, be nonallergenic and nonsensitized; have rapid action: be non-toxic and non-irritating; be chemically and pharmacologically compatible with other ingredients of the system; be chemically stable and not undergo discoloration; and should be readily and adequately soluble in the appropriate vehicles.
  • the stabilized PVP-I solutions of the present invention possess the beneficial properties outlined above.
  • the stabilized PVP-I solutions of the present invention when prepared in suitable concentrations for ophthalmic use, have microbicidal activity as effective as that of commercially available antibiotic solutions such as Neosporin and Garamycin, and are similar to such products with respect to their non-irritating properties.
  • the stabilized microbicidal PVP-I solutions of the present invention are useful as microbicidal ophthalmic preparations, as combination products (e.g. in combination with local anesthetics, anti-inflammatories, etc.) for example, for ophthalmic and otic use.
  • the stabilized PVP-I solutions of the present invention are useful in ophthalmic products and the like as a preservative.
  • the glass containers for storing the iodophor solutions of the present invention are those which are composed of pharmaceutically acceptable glass, as defined in the U.S. Pharmacopeia or National Formulary (N.F.). Both the U.S.P. and N.F. define the same four glass types (highly resistant, borosilicate glass, treated soda-lime glass, soda-lime glass, and general purpose soda-lime glass) and their alkalinity limits.
  • the glass containers may be colorless, opaque or colored. There are four types of clear containers available, colorless, green, blue and amber. Amber glass is most preferred.
  • a non-isotonic 0.3% PVP-I solution was prepared which was not buffered at the above pH of 5.4, but only with adjusting the pH at 4.0.
  • the formula for this solution was as follows: 0.3% PVP-I, NON-BUFFERED, NON-ISOTONIC Ingredient Percent PVP-I 0.30 Igepal® CO-630 0.004 Methocel® E4M 0.5 Sodium Hydroxide qs to pH 4.0 Purified water qs to 100
  • PVP-I solutions having concentrations of 0.02%, 0.03%, 0.04%, and 0.05% were prepared in accordance with the formulas provided in Examples 3-6. These solutions were then tested for In vitro microbiology against two commercially available products.
  • Killing time tests were conducted with a series of log phase cultures of gram negative and gram positive organisms including Gentamicin resistant Pseudomonas aeruginosa and selected viruses. Controls used were ophthalmic preparations of Neosporin and Garamycin (Comparative Examples A and B, respectively). Bacterial samples were taken at 30 seconds, 1, 2, 5, 10 and 15 minutes and transferred into culture media containing inactivators for iodine. Similarly, virus killing time tests were sampled at one minute and transferred into inactivating media.
  • aeruginosa Gm+ 5 min ⁇ 30 ⁇ 30 ⁇ 30 >15min >15min Ps. aeruginosa, Gm+ 1 min ⁇ 30 ⁇ 30 ⁇ 30 >15min >15min S. aureus 1 min ⁇ 30 ⁇ 30 ⁇ 30 >15min ⁇ 30 E. coli ⁇ 30 ⁇ 30 ⁇ 30 ⁇ 30 ⁇ 30 5min S. pneumoniae ⁇ 30 ⁇ 30 ⁇ 30 ⁇ 30 >15min ⁇ 30 N.
  • Example 8 The PVP-I ophthalmic Drops of Example 8 were tested for ocular safety before the lot was released for human clinical trials. Two vials were taken from sterile vials set aside for clinical trials. A 0.1 ml sample of each tested via was instilled into one eye of each of six albino rabbits. The animal was observed for 72 hours for signs of ocular corneal or conjunctival irritation. Results obtained at the end of the 72 hour test period found the contents of both test vials to be non-irritating in this standard-ocular safety test.
  • Example 11 a study was conducted similar to that in Examples 7 - 10 above, with the antimicrobial effect of PVP-I solutions as dilute as 0.12% (Example 11) and as concentrated as 0.060% (Example 12) were determined, respectively.
  • the formulations for these results are set forth in Tables 11 and 12, respectively, and the results are provided in Table 13 below: 0.12% PVP-I, Non-buffered, Isotonic Ingredient Percent PVP-I 0.12 Igepal® CO-630 0.004 Methocel® E4M 0.50 Sodium Chloride 0.90 Sodium Hydroxide (5%) qs to pH 4.0 Purified water qs to 100 0.6% PVP-I, Non-buffered, Isotonic Ingredient Percent PVP-I 0.60 Igepal® CO-630 0.004 Methocel® E4M 0.50 Sodium Chloride 0.90 Sodium Hydroxide (5%) qs to pH 4.0 Purified water qs to 100 TEST - In vitro killing Organism
  • gonorrhoreae >15 min. ⁇ 30 sec.
  • Ps. aeruginosa >15 min. ⁇ 30 sec.
  • E. coli >15 min. ⁇ 30 sec.
  • PVP-I solutions at least as dilute as 0.12% PVP-I (0.012% available iodine) and at least as concentrated as 0.060% PVP-I are also effective as an anti-microbial.
  • rabbit eye irritation studies were conducted in order to compare the properties of unbuffered, non-isotonic solutions of PVP-I at pH 4 (Example 13) and unbuffered isotonic PVP-I solutions at pH 4 (Example 14) to isotonic solutions of PVP-I buffered to a pH of 5.6 (Comparative Example C; not stable).
  • rabbit eye irritation studies were conducted with a saline solution control and two commercially available products, Neosporin and Herplex.
  • Example 13 14 C Ingredient % % % PVP-I 0.3 0.3 0.3 Igepal® Co-630 0.004 0.004 0.004 Methocel® E4M 0.5 0.5 0.5 0.5 Sodium Chloride 0.50 0.0 0.90 Monobasic Sodium Phosphate 0.76 0.0 0.0 Dibasic Sodium Phosphate 0.047 0.0 0.0 Sodium Hydroxide(5%) qs to pH 5.6 qs to pH 4.0 qs to pH 4.0 Purified water qs to 100 qs to 100 qs to 100 qs to 100 qs to 100
  • Example 15 a randomized paired comparison comfort evaluation was conducted in 30 normal human volunteers with a solution of stabilized, unbuffered isotonic 0.3% PVP-I having the formulation provided for Example 14, with Garamycin ophthalmic solution and Sodium Sulamyd ophthalmic solution. The results of this study revealed that there was statistically no significant differences in the discomfort between all three solutions.

Landscapes

  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Inorganic Chemistry (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Lubricants (AREA)
  • Emulsifying, Dispersing, Foam-Producing Or Wetting Agents (AREA)
  • Hydrogenated Pyridines (AREA)

Claims (12)

  1. Solution de iodophore stabilisée comprenant une quantité efficace microbicide d'iode disponible inférieure à celle d'une solution à 1,0 % en poids de povidone - iode et un agent d'alcalinisation, ladite solution n'étant pas tamponnée.
  2. Solution selon la revendication 1, dans laquelle l'iode disponible est fourni par la povidone - iode.
  3. Solution selon la revendication 1 ou 2, dans laquelle ledit agent d'alcalinisation est choisi dans le groupe consistant en l'hydroxyde de sodium, l'hydroxyde de potassium, le bicarbonate de sodium, le phosphate disodique et leurs mélanges.
  4. Solution selon l'une quelconque des revendications 1 à 3, comprenant initialement une quantité d'iode disponible correspondant à celle d'une solution de povidone - iode de 0,12 à 0,72 % ( poids/volume ).
  5. Solution selon la revendication 4, comprenant initialement de 0,03 % à 0,06 % ( poids / volume ) d'iode disponible.
  6. Solution selon l'une quelconque des revendications 1 à 5, dans laquelle ledit agent d'alcalinisation est présent en quantité suffisante pour régler le pH de la solution à une valeur initiale de 2 - 6,5.
  7. Solution selon la revendication 6, dans laquelle ledit agent d'alcalinisation est présent en quantité suffisante pour régler le pH de la solution à une valeur initiale de 2 - 4,5.
  8. Solution selon la revendication 6, dans laquelle ledit agent d'alcalinisation est présent en quantité suffisante pour régler le pH de la solution à une valeur initiale de 4 - 4,5.
  9. Solution ophtalmologique stabilisée comprenant la solution de iodophore stabilisée selon l'une quelconque des revendications 1 à 8.
  10. Solution ophtalmologique selon la revendication 9, qui présente une isotonie avec le fluide lacrimal humain.
  11. Solution ophtalmologique selon la revendication 10, que l'on rend isotonique avec le fluide lacrimal humain par une quantité efficace de chlorure de sodium.
  12. Solution ophtalmologique selon l'une quelconque des revendications 9 à 11, qui est sensiblement non-irritante pour l'oeil humain.
EP92106500A 1991-07-16 1992-04-15 Solutions de PVP-I stabilisées Expired - Lifetime EP0526695B1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US730462 1985-05-06
US07/730,462 US5126127A (en) 1991-07-16 1991-07-16 Stabilized PVP-I solutions

Publications (2)

Publication Number Publication Date
EP0526695A1 EP0526695A1 (fr) 1993-02-10
EP0526695B1 true EP0526695B1 (fr) 1998-02-11

Family

ID=24935466

Family Applications (1)

Application Number Title Priority Date Filing Date
EP92106500A Expired - Lifetime EP0526695B1 (fr) 1991-07-16 1992-04-15 Solutions de PVP-I stabilisées

Country Status (16)

Country Link
US (1) US5126127A (fr)
EP (1) EP0526695B1 (fr)
JP (1) JP3531945B2 (fr)
KR (1) KR100191873B1 (fr)
AT (1) ATE163130T1 (fr)
AU (1) AU646745B2 (fr)
CA (1) CA2062001C (fr)
DE (1) DE69224416T2 (fr)
DK (1) DK0526695T3 (fr)
EG (1) EG19995A (fr)
ES (1) ES2111581T3 (fr)
FI (1) FI114443B (fr)
IE (1) IE920796A1 (fr)
IL (1) IL101079A (fr)
NO (1) NO306379B1 (fr)
ZA (1) ZA921365B (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021248196A1 (fr) * 2020-06-10 2021-12-16 Firebrick Pharma Limited Formulations virucides améliorées
US11246887B2 (en) 2019-06-10 2022-02-15 Firebrick Pharma Limited Prevention of infection by highly pathogenic viruses using topical application of povidone-iodine on mucous membranes
AU2021203846B2 (en) * 2021-06-10 2022-11-24 Firebrick Pharma Limited Virucidal formulations containing povidone-iodine

Families Citing this family (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993006911A1 (fr) * 1991-10-08 1993-04-15 Isp Investments Inc. Procede de traitement du sang
GB9306296D0 (en) * 1993-03-26 1993-05-19 Diversey Corp Improved iodophors,production and use thereof
DE9312509U1 (de) * 1993-08-20 1993-10-28 Euro-Celtique S.A., Luxemburg/Luxembourg Präparate zur äußeren Verabreichung von antiseptischen und/oder die Wundheilung fördernden Wirkstoffen
JP3108262B2 (ja) * 1993-12-22 2000-11-13 明治製菓株式会社 研磨剤を含有しない口腔用半練状製剤
US6605110B2 (en) 2001-06-29 2003-08-12 Advanced Cardiovascular Systems, Inc. Stent with enhanced bendability and flexibility
ATE371436T1 (de) 2003-05-19 2007-09-15 Euro Celtique Sa Trockene liposomale pvp-jod zubereitungen
US20050262811A1 (en) * 2004-05-27 2005-12-01 Mahmood Mohiuddin Sterilization process for iodine-containing antimicrobial topical solutions
AU2013203462B2 (en) * 2006-03-14 2016-08-04 Cls Pharmaceuticals, Inc. Ophthalmic compositions comprising povidone-iodine
US7767217B2 (en) * 2006-03-14 2010-08-03 Foresight Biotherapeutics Ophthalmic compositions comprising povidone-iodine
AU2016253668B2 (en) * 2006-03-14 2018-12-06 Cls Pharmaceuticals, Inc. Ophthalmic compositions comprising povidone-iodine
JP5083502B2 (ja) * 2006-12-25 2012-11-28 ライオン株式会社 眼科用組成物
US20080172032A1 (en) * 2007-01-11 2008-07-17 James Pitzer Gills Method for preventing tissue damage associated with irrigation of tissue with an antimicrobial solution
EP2291081B1 (fr) * 2008-06-12 2020-06-03 Foresight Biotherapeutics, Inc. La povidone iodée, nouveau conservateur innovant pour compositions ophtalmiques
CA2784492C (fr) * 2009-12-15 2020-06-30 Foresight Biotherapeutics, Inc. Compositions ophtalmiques anti-irritation a base de povidone iodee
JP5367597B2 (ja) 2010-01-18 2013-12-11 株式会社オフテクス コンタクトレンズ洗浄用有核錠及びそれを含むコンタクトレンズ洗浄用製剤、並びにコンタクトレンズ洗浄方法
GB201114725D0 (en) 2011-08-25 2011-10-12 Altacor Ltd Ophthalmic formulations
TW201325601A (zh) * 2011-09-16 2013-07-01 Foresight Biotherapeutics Inc 安定之普維酮－碘組成物
ES2974663T3 (es) 2012-09-12 2024-07-01 Novaliq Gmbh Alcanos semifluorados para uso en la solubilización de meibomio
CA2883003C (fr) 2012-09-12 2021-11-16 Novaliq Gmbh Compositions d'alcanes semifluores
US9770466B2 (en) 2015-07-02 2017-09-26 Veloce Biopharma, Llc Ophthalmic composition and methods of use
US20180200289A1 (en) * 2015-07-02 2018-07-19 Veloce Biopharma, Llc Novel ophthalmic composition and methods of use
EP3612228B1 (fr) 2017-04-21 2023-08-23 Dermaliq Therapeutics, Inc. Compositions d'iode
IT201700068170A1 (it) * 2017-06-20 2018-12-20 Iromed Group S R L Composizione disinfettante per uso oftalmico
EP3672572A4 (fr) * 2017-08-22 2021-01-06 Veloce BioPharma, LLC Nouvelle composition ophtalmique et méthodes d'utilisation
JP6941889B2 (ja) 2017-09-02 2021-09-29 アイビュー セラピューティクス、インコーポレイテッド インサイチュゲル形成医薬組成物および副鼻腔疾患のためのその使用
JP7500550B2 (ja) 2018-10-12 2024-06-17 ノバリック ゲーエムベーハー 乾性眼疾患の治療のための眼科用組成物
KR20200081160A (ko) 2018-12-27 2020-07-07 유한회사 플루켐 염화나트륨 함유 포비돈 요오드 안정 조성물 및 방법
US20210401878A1 (en) * 2019-08-18 2021-12-30 Iview Therapeutics, Inc. Stable Pharmaceutical Articles Containing Dilute Povidone Iodine Formulations
KR102434736B1 (ko) 2021-11-04 2022-08-23 (주)씨에스하이테크플러스 신재생에너지를 이용한 에너지자립형 냉난방 시스템 및 방법

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SE7902893L (sv) * 1979-04-02 1980-10-03 Astra Chem Prod Ab Desinfektionsmedel
US4364929A (en) * 1979-04-02 1982-12-21 The Purdue Frederick Company Germicidal colloidal lubricating gels and method of producing the same
US4401651A (en) * 1979-04-18 1983-08-30 Knutson Richard A Wound-healing compositions containing povidone-iodine
US4526751A (en) * 1983-12-09 1985-07-02 Gartner William J Germicidal solutions effective for solid surface disinfection
WO1989000044A1 (fr) * 1987-07-07 1989-01-12 Santen Pharmaceutical Co., Ltd. Larme artificielle
CA1303503C (fr) * 1987-11-10 1992-06-16 Marc Plamondon Solution ophtalmique comportant un complexe iode-polyvinylpyrrolidone
KR920002329B1 (ko) * 1987-12-25 1992-03-21 산뗑 세이야꾸 가부시끼가이샤 항-알레르기성 점안제
US4939272A (en) * 1989-05-05 1990-07-03 Gaf Chemicals Corporation Water soluble complexes of polyvinylpyrrolidone, hydrogen chloride and iodine and process for making the same
NL9002049A (nl) * 1990-09-18 1992-04-16 Dagra Pharma Bv Oogheelkundig preparaat dat een povidon-joodoplossing bevat.

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11246887B2 (en) 2019-06-10 2022-02-15 Firebrick Pharma Limited Prevention of infection by highly pathogenic viruses using topical application of povidone-iodine on mucous membranes
US11969441B2 (en) 2019-06-10 2024-04-30 Firebrick Pharma Limited Prevention of infection by highly pathogenic viruses using topical application of povidone-iodine on mucous membranes
WO2021248196A1 (fr) * 2020-06-10 2021-12-16 Firebrick Pharma Limited Formulations virucides améliorées
AU2021203846B2 (en) * 2021-06-10 2022-11-24 Firebrick Pharma Limited Virucidal formulations containing povidone-iodine

Also Published As

Publication number Publication date
IL101079A0 (en) 1992-11-15
EP0526695A1 (fr) 1993-02-10
DE69224416D1 (de) 1998-03-19
ATE163130T1 (de) 1998-02-15
JP3531945B2 (ja) 2004-05-31
FI922906A (fi) 1993-01-17
JPH0570356A (ja) 1993-03-23
EG19995A (en) 1997-01-30
IL101079A (en) 1997-01-10
AU646745B2 (en) 1994-03-03
AU1942792A (en) 1994-01-13
NO922793L (no) 1993-01-18
CA2062001C (fr) 1999-03-02
DK0526695T3 (da) 1998-09-23
US5126127A (en) 1992-06-30
FI114443B (fi) 2004-10-29
CA2062001A1 (fr) 1993-01-17
KR930001914A (ko) 1993-02-22
NO306379B1 (no) 1999-11-01
ES2111581T3 (es) 1998-03-16
KR100191873B1 (ko) 1999-06-15
FI922906A0 (fi) 1992-06-22
NO922793D0 (no) 1992-07-15
DE69224416T2 (de) 1998-07-30
IE920796A1 (en) 1993-01-27
ZA921365B (en) 1992-11-25

Similar Documents

Publication Publication Date Title
EP0526695B1 (fr) Solutions de PVP-I stabilisées
KR100884711B1 (ko) 외용 투여용 올로파타딘 제제
ES2246491T3 (es) Utilizacion de complejos borato-poliol en composiciones oftalmicas.
KR100366676B1 (ko) 안과용 조성물에 저분자량 아미노 알코올을 사용하는 방법
US4312833A (en) Sterilizing hydrophilic contact lenses
KR20000036193A (ko) 콘택트 렌즈를 재습윤시키고 안구 건조감을 경감시키는 방법 및조성물
AU2002310461A1 (en) Olopatadine formulations for topical administation
EP2747772B1 (fr) Formulation ophtalmique
US20090239775A1 (en) Ophthalmic solutions displaying improved efficacy
KR20190123716A (ko) 연화성 국소 소독제
EP0674532B1 (fr) Solution de desinfection de lentilles de contact renfermant un agent oxydant et de la pyrrolidone de polyvinyle
CN101861139A (zh) 含有盐酸莫西沙星和磷酸地塞米松的局部眼或耳用溶液制剂
US20210401878A1 (en) Stable Pharmaceutical Articles Containing Dilute Povidone Iodine Formulations
US5242985A (en) Aqueous stable complex of a strongly swellable, moderately crosslinked polyvinylpyrrolidone and iodine
EP2730292A1 (fr) Composition ophtalmique aqueuse
CN114306228A (zh) 一种地夸磷索钠滴眼液及其制备方法
AU2010236505B2 (en) Aqueous ophthalmic compositions containing anionic therapeutic agents
CA3198150A1 (fr) Formulation a base de polyhexamethylene biguanide destinee a etre utilisee dans le traitement de la keratite a acanthamoeba et/ou d'infections fongiques

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IT LI LU NL PT SE

17P Request for examination filed

Effective date: 19930810

17Q First examination report despatched

Effective date: 19941208

GRAG Despatch of communication of intention to grant

Free format text: ORIGINAL CODE: EPIDOS AGRA

GRAG Despatch of communication of intention to grant

Free format text: ORIGINAL CODE: EPIDOS AGRA

GRAG Despatch of communication of intention to grant

Free format text: ORIGINAL CODE: EPIDOS AGRA

GRAH Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOS IGRA

GRAH Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOS IGRA

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AT BE CH DE DK ES FR GB GR IT LI LU NL PT SE

REF Corresponds to:

Ref document number: 163130

Country of ref document: AT

Date of ref document: 19980215

Kind code of ref document: T

REG Reference to a national code

Ref country code: CH

Ref legal event code: EP

REG Reference to a national code

Ref country code: CH

Ref legal event code: NV

Representative=s name: R. A. EGLI & CO. PATENTANWAELTE

ITF It: translation for a ep patent filed
REG Reference to a national code

Ref country code: ES

Ref legal event code: FG2A

Ref document number: 2111581

Country of ref document: ES

Kind code of ref document: T3

REF Corresponds to:

Ref document number: 69224416

Country of ref document: DE

Date of ref document: 19980319

ET Fr: translation filed
REG Reference to a national code

Ref country code: PT

Ref legal event code: SC4A

Free format text: AVAILABILITY OF NATIONAL TRANSLATION

Effective date: 19980213

REG Reference to a national code

Ref country code: DK

Ref legal event code: T3

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

26N No opposition filed
REG Reference to a national code

Ref country code: GB

Ref legal event code: IF02

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: AT

Payment date: 20050407

Year of fee payment: 14

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: FR

Payment date: 20050411

Year of fee payment: 14

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: DK

Payment date: 20050412

Year of fee payment: 14

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: NL

Payment date: 20050413

Year of fee payment: 14

Ref country code: GB

Payment date: 20050413

Year of fee payment: 14

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: PT

Payment date: 20050415

Year of fee payment: 14

Ref country code: DE

Payment date: 20050415

Year of fee payment: 14

Ref country code: CH

Payment date: 20050415

Year of fee payment: 14

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: SE

Payment date: 20050419

Year of fee payment: 14

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: GR

Payment date: 20050421

Year of fee payment: 14

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: LU

Payment date: 20050425

Year of fee payment: 14

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: ES

Payment date: 20050506

Year of fee payment: 14

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: BE

Payment date: 20050511

Year of fee payment: 14

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: GB

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20060415

Ref country code: AT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20060415

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20060416

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: ES

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20060417

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20060430

Ref country code: LI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20060430

Ref country code: CH

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20060430

Ref country code: BE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20060430

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: IT

Payment date: 20060430

Year of fee payment: 15

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: DK

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20060501

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: PT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20061016

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: NL

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20061101

Ref country code: DE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20061101

REG Reference to a national code

Ref country code: DK

Ref legal event code: EBP

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

EUG Se: european patent has lapsed
GBPC Gb: european patent ceased through non-payment of renewal fee

Effective date: 20060415

REG Reference to a national code

Ref country code: PT

Ref legal event code: MM4A

Free format text: LAPSE DUE TO NON-PAYMENT OF FEES

Effective date: 20061016

NLV4 Nl: lapsed or anulled due to non-payment of the annual fee

Effective date: 20061101

REG Reference to a national code

Ref country code: FR

Ref legal event code: ST

Effective date: 20061230

REG Reference to a national code

Ref country code: ES

Ref legal event code: FD2A

Effective date: 20060417

BERE Be: lapsed

Owner name: S.A. *EURO-CELTIQUE

Effective date: 20060430

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: FR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20060502

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: GR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20061102

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20070415